Alzheimer's disease and drug delivery across the blood-brain barrier: approaches and challenges.

Alzheimer's disease (AD) is a diverse disease with a complex pathophysiology. The presence of extracellular ß-amyloid deposition as neuritic plaques and intracellular accumulation of hyper-phosphorylated tau as neurofibrillary tangles remain the core neuropathologic criteria for diagnosing Alzheimer's disease. Nonetheless, several recent basic discoveries have revealed significant pathogenic roles for other essential cellular and molecular processes. Previously, there were not so many disease-modifying medications (DMT) available as drug distribution through the blood-brain barrier (BBB) is difficult due to its nature, especially drugs of polypeptides nature and proteins. Recently FDA has approved lecanemab as DMT for its proven efficacy. It is also complicated to deliver drugs for diseases like epilepsy or any brain tumor due to the limitations of the BBB. After the advancements in the drug delivery system, different techniques are used to transport the medication across the BBB. Other methods are used, like enhancement of brain blood vessel fluidity by liposomes, infusion of hyperosmotic solutions, and local intracerebral implants, but these are invasive approaches. Non-invasive approaches include the formulation of nanoparticles and their coating with polymers. This review article emphasizes all the above-mentioned techniques, procedures, and challenges to transporting medicines across the BBB. It summarizes the most recent literature dealing with drug delivery across the BBB.

Plant Polyphenols and Their Potential Benefits on Cardiovascular Health: A Review.

Fruits, vegetables, and other food items contain phytochemicals or secondary metabolites which may be considered non-essential nutrients but have medicinal importance. These dietary phytochemicals exhibit chemopreventive and therapeutic effects against numerous diseases. Polyphenols are secondary metabolites found in vegetables, fruits, and grains. These compounds exhibit several health benefits such as immune modulators, vasodilators, and antioxidants. This review focuses on recent studies on using dietary polyphenols to treat cardiovascular disorders, atherosclerosis, and vascular endothelium deficits. We focus on exploring the safety of highly effective polyphenols to ensure their maximum impact on cardiac abnormalities and discuss recent epidemiological evidence and intervention trials related to these properties. Kaempferol, quercetin, and resveratrol prevent oxidative stress by regulating proteins that induce oxidation in heart tissues. In addition, polyphenols modulate the tone of the endothelium of vessels by releasing nitric oxide (NO) and reducing low-density lipoprotein (LDL) oxidation to prevent atherosclerosis. In cardiomyocytes, polyphenols suppress the expression of inflammatory markers and inhibit the production of inflammation markers to exert an anti-inflammatory response. Consequently, heart diseases such as strokes, hypertension, heart failure, and ischemic heart disease could be prevented by dietary polyphenols.

Conocarpus lancifolius (Combretaceae): Pharmacological Effects, LC-ESI-MS/MS Profiling and In Silico Attributes.

In folklore medicine, Conocarpus lancifolius is used to treat various illnesses. The main objective of this study was a comprehensive investigation of Conocarpus lancifolius leaf aqueous extract (CLAE) for its antioxidant, cardioprotective, anxiolytic, antidepressant and memory-enhancing capabilities by using different in vitro, in vivo and in silico models. The in vitro experimentation revealed that CLAE consumed an ample amount of total phenolics (67.70 ± 0.15 µg GAE/mg) and flavonoids (47.54 ± 0.45 µg QE/mg) with stronger antiradical effects through DPPH (IC50 = 16.66 ± 0.42 µg/mL), TAC (77.33 ± 0.41 µg AAE/mg) and TRP (79.11 ± 0.67 µg GAE/mg) assays. The extract also displayed suitable acetylcholinesterase (AChE) inhibitory (IC50 = 110.13 ± 1.71 µg/mL) activity through a modified Ellman's method. The toxicology examination presented no mortality or any signs of clinical toxicity in both single-dose and repeated-dose tests. In line with the cardioprotective study, the pretreatment of CLAE was found to be effective in relieving the isoproterenol (ISO)-induced myocardial injury in rats by normalizing the heart weight index, serum cardiac biomarkers, lipid profile and various histopathological variations. In the noise-stress-induced model for behavior attributes, the results demonstrated that CLAE has the tendency to increase the time spent in the central zone and elevated open arms in the open field and elevated plus maze tests (examined for anxiety assessment), reduced periods of immobility in the forced swimming test (for depression) and improved recognition and working memory in the novel object recognition and Morris water maze tests, respectively. Moreover, the LC-ESI-MS/MS profiling predicted 53 phytocompounds in CLAE. The drug-likeness and ADMET analysis exhibited that the majority of the identified compounds have reasonable physicochemical and pharmacokinetic profiles. The co-expression of molecular docking and network analysis indicated that top-ranked CLAE phytoconstituents act efficiently against the key proteins and target multiple signaling pathways to exert its cardiovascular-protectant, anxiolytic, antidepressant and memory-enhancing activity. Hence, this artifact illustrates that the observed biological properties of CLAE elucidate its significance as a sustainable source of bioactive phytochemicals, which appears to be advantageous for pursuing further studies for the development of new therapeutic agents of desired interest.

Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms.

Type II diabetes mellitus and its related complications are growing public health problems. Many natural products present in our diet, including polyphenols, can be used in treating and managing type II diabetes mellitus and different diseases, owing to their numerous biological properties. Anthocyanins, flavonols, stilbenes, curcuminoids, hesperidin, hesperetin, naringenin, and phenolic acids are common polyphenols found in blueberries, chokeberries, sea-buckthorn, mulberries, turmeric, citrus fruits, and cereals. These compounds exhibit antidiabetic effects through different pathways. Accordingly, this review presents an overview of the most recent developments in using food polyphenols for managing and treating type II diabetes mellitus, along with various mechanisms. In addition, the present work summarizes the literature about the anti-diabetic effect of food polyphenols and evaluates their potential as complementary or alternative medicines to treat type II diabetes mellitus. Results obtained from this survey show that anthocyanins, flavonols, stilbenes, curcuminoids, and phenolic acids can manage diabetes mellitus by protecting pancreatic ß-cells against glucose toxicity, promoting ß-cell proliferation, reducing ß-cell apoptosis, and inhibiting α-glucosidases or α-amylase. In addition, these phenolic compounds exhibit antioxidant anti-inflammatory activities, modulate carbohydrate and lipid metabolism, optimize oxidative stress, reduce insulin resistance, and stimulate the pancreas to secrete insulin. They also activate insulin signaling and inhibit digestive enzymes, regulate intestinal microbiota, improve adipose tissue metabolism, inhibit glucose absorption, and inhibit the formation of advanced glycation end products. However, insufficient data are available on the effective mechanisms necessary to manage diabetes.

Mechanistic insights of Cucumis melo L. seeds for gastrointestinal muscle spasms through calcium signaling pathway-related gene regulation networks in WGCNA and in vitro, in vivo studies.

BACKGROUND: In addition to the nutritional benefits of Cucumis melo L., herbalists in Pakistan and India employ seeds to treat various ailments. This study aimed to determine the regulatory role of C. melo seeds in calcium-mediated smooth muscle contraction. METHODS: We identified and quantified the phytochemicals of C. melo with LC ESI-MS/MS and HPLC, then conducted in vitro and in vivo tests to confirm the involvement in smooth muscle relaxation. Then, diarrhea-predominant irritable bowel syndrome gene datasets from NCBI GEO were acquired, DEGs and WGCNA followed by functional enrichment analysis. Next, molecular docking of key genes was performed. RESULTS: The quantification of C. melo seeds revealed concentrations of rutin, kaempferol, and quercetin were 702.38 µg/g, 686.29 µg/g, and 658.41 µg/g, respectively. In vitro experiments revealed that C. melo seeds had a dose-dependent relaxant effect for potassium chloride (80 mM)-induced spastic contraction and exhibited calcium antagonistic response in calcium dose-response curves. In in vivo studies, Cm.EtOH exhibited antidiarrheal, antiperistaltic, and antisecretory effects. The functional enrichment of WGCNA and DEGs IBS-associated pathogenic genes, including those involved in calcium-mediated signaling, MAPK cascade, and inflammatory responses. MAPK1 and PIK3CG were identified as key genes with greater binding affinity with rutin, quercitrin, and kaempferol in molecular docking. CONCLUSIONS: The bronchodilator and antidiarrheal effects of C. melo were produced by altering the regulatory genes of calcium-mediated smooth contraction.

Cardioprotective and hypotensive mechanistic insights of hydroethanolic extract of Cucumis melo L. kernels in isoprenaline-induced cardiotoxicity based on metabolomics and in silico electrophysiological models.

Background: Cardiovascular diseases (CVD) continue to threaten health worldwide, and account for a significant portion of deaths and illnesses. In both developing and industrialized nations, they challenge their health systems. There are several traditional uses of Cucurbitaceae seeds in Pakistan, India, Iran, and China, including treating cardiovascular, neurological, and urogenital diseases. Methods: In the present work, integrated techniques of metabolomics profiling and computational cardiomyocyte stimulation were used to investigate possible mechanisms of C. melo in isoprenaline (ISO)-induced myocardial infarction. In vitro, vasoconstrictions, paired atria, and in vivo invasive blood pressure measurement models were performed to explore the mechanism of action of C. melo hydroethanolic seed extract (Cm-EtOH). Results: Results showed that Cm-EtOH demonstrates NO-based endothelium-derived relaxing factor (EDRF) vasorelaxant response, negative chronotropic and inotropic response in the atrium, and hypotensive effects in normotensive rats. Results also revealed that Cm-EtOH decreases cardiomyocyte hypertrophy and reverts the altered gene expressions, biochemical, and metabolites in ISO-induced myocardial infarction (MI) rats. The extract additionally reversed ISO-induced MI-induced oxidative stress, energy consumption, and amino acid metabolism. Moreover, C. melo seeds increased EDRF function, energy production, and antioxidant capacity to treat myocardial and vascular disorders. In computational cardiomyocyte simulation, gallic acid reduced action potential duration, upstroke velocity (dV/dtmax), and effective refractory period. Conclusion: This study highlights the therapeutic potential of C. melo seeds to treat cardiovascular diseases and provides mechanistic insight into its antihypertensive and cardioprotective activities.

Integrated Mechanisms of Polarity-Based Extracts of Cucumis melo L. Seed Kernels for Airway Smooth Muscle Relaxation via Key Signaling Pathways Based on WGCNA, In Vivo, and In Vitro Analyses.

The present study aimed to determine the mechanisms responsible for calcium-mediated smooth muscle contractions in C. melo seeds. The phytochemicals of C. melo were identified and quantified with the aid of Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC/ESI-MS/MS) and high-performance liquid chromatography (HPLC), and then tested in-vitro and in vivo to confirm involvement in smooth muscle relaxation. Allergic asthma gene datasets were acquired from the NCBI gene expression omnibus (GEO) and differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis were conducted. Additionally, molecular docking of key genes was carried out. Kaempferol, rutin, and quercetin are identified as phytochemical constituents of C. melo seeds. Results indicated that C. melo seeds exhibit a dose-dependent relaxant effect for potassium chloride (80 mM)- induced spastic contraction and calcium antagonistic response in calcium dose-response curves. The functional enrichment of WGCNA and DEG asthma-associated pathogenic genes showed cytokine-mediated pathways and inflammatory responses. Furthermore, CACNA1A, IL2RB, and NOS2 were identified as key genes with greater binding affinity with rutin, quercitrin, and kaempferol in molecular docking. These results show that the bronchodilator and antidiarrheal effects of C. melo were produced by altering the regulatory genes of calcium-mediated smooth muscle contraction.

Possible Mechanisms Underlying the Antispasmodic, Bronchodilator, and Antidiarrheal Activities of Polarity-Based Extracts of Cucumis sativus L. Seeds in In Silico, In Vitro, and In Vivo Studies.

Apart from the nutritional value, Cucumis sativus L. has also been used in the traditional medicine of Iran, Pakistan, and India. Its seeds are used by herbalists to treat gastrointestinal, respiratory, and urinary problems. However, more investigations are required to explain its mechanisms for treating GI, respiratory, and urinary diseases. Accordingly, the aim of the present work was to investigate the antispasmodic, bronchodilator, and antidiarrheal activities of C. sativus seeds extracts and the underlying mechanisms of action. For this purpose, sequential extracts of C. sativus seeds were prepared in n-hexane, dichloromethane, ethanol, and water. Bioactive compounds in C. sativus seed extracts were identified and quantified by utilizing LC ESI-MS/MS and HPLC. Moreover, network pharmacology and molecular docking were employed to examine the antispasmodic and bronchodilator effects of the bioactive substances in the extracts. In vitro and in vivo experiments were also conducted to validate the mechanistic insights gained from the in silico analysis. Results indicated the presence of kaempferol with a concentration of 813.74 µg/g (highest concentration) in the seed extract of C. sativus, followed by quercetin (713.83 µg/g), narcissin (681.87 µg/g), and orientin (676.19 µg/g). In silico investigations demonstrated that the bioactive chemicals in C. sativus seeds inhibited the expression of the target genes involved in smooth muscle contraction and calcium-mediated signaling. Sequential seed extracts of C. sativus caused a dose-dependent relaxant response for spasmolytic reaction and resulted in a relaxation of K+ (80 mM) spastic contraction. In animal models, C. sativus seed extracts exhibited partial or complete antiperistalsis, antidiarrheal, and antisecretory actions. By modulating the contractile response through calcium-mediated signaling target proteins, C. sativus seeds generated bronchodilator, antispasmodic, and antidiarrheal therapeutic effects.

Antispasmodic activity of the ethanol extract of Citrullus lanatus seeds: Justifying ethnomedicinal use in Pakistan to treat asthma and diarrhea.

ETHNOPHARMACOLOGICAL RELEVANCE: Citrullus lanatus (Thunb.) belongs to the ground family, Cucurbitaceae, known for edible fruit. Besides nutritional benefits, the traditional herbal practitioners in Pakistan and India used their seeds to treat gastrointestinal, respiratory, and urinary disorders. In Northern Sudan, its seeds are often used as a laxative. Its root is laxative and emetic at a high dose. Its seeds are also used to treat bedwetting and urinary tract obstruction. AIM OF THE STUDY: This study aimed to elucidate the multi-target mechanisms of Citrullus lanatus seeds to treat asthma and diarrhea. The pharmacological experiments were designed and conducted, along with the pharmacology network and molecular docking predictions, to verify the seeds biopotency for antispasmodic and bronchodilator properties. METHODS: LC ESI-MS/MS were performed to identify the potentially active compounds in hydroethanolic extract of Citrullus lanatus seeds, then to quantify them by HPLC. The quantified bioactive compounds of Citrullus lanatus, i.e., stigmasterol, quinic acid, malic acid, epicatechin, caffeic acid, rutin, p-coumaric acid, quercetin, ferulic acid, scopoletin, apigenin, and kaempferol were subjected to in silico studies for molecular docking. The hydroethanolic extract of Citrullus lanatus seeds was examined on isolated rabbit tissue, i.e., jejunum, trachea, and urinary bladder. The antiperistalsis, antidiarrheal and antisecretory studies were also performed in animal models. RESULTS: In silico studies revealed that bioactive compounds of C. lanatus seeds interfere with asthma and diarrhea-associated target genes, which are a member of calcium mediate signaling, regulation of cytosolic calcium concentration, smooth muscle contraction, and inflammatory responses. It was also found that rutin, quercetin, kaempferol, and scopoletin were stronger binding to voltage-gated calcium channels, calcium/calmodulin-dependent protein kinase, myosin light chain kinase, and phosphoinositide phospholipase C, thus, exerting calcium channel blocker activity. The hydroethanolic extract of C. lanatus seeds exerted a concentration-dependent relaxant response for the spasmolytic response on isolated jejunum and trachea preparations and caused relaxation of spastic contraction of K+ (80 mM). Furthermore, it caused a non-parallel rightward shift with suppression of calcium concentration-response curves. In animal models, the Cl.EtOH showed antiperistalsis, antidiarrheal and antisecretory response. CONCLUSION: Thus, we confirm Citrullus lanatus seeds have some medicinal effects by regulating the contractile response through target proteins of calcium mediates signaling and can be a promising component in the medical treatment for asthma and diarrhea.

Metabolomics based mechanistic insights to vasorelaxant and cardioprotective effect of ethanolic extract of Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds in isoproterenol induced myocardial infraction.

BACKGROUND: Cardiovascular diseases (CVDs) are a significant cause of morbidity and death in the current world, posing a challenge to both developing and industrialized nation's health systems. Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds have long been utilized to supplement and enhance health and treat cardiovascular illnesses. However, its treatments for CVDs are still unknown. More research is required to fully comprehend the impact of C. lanatus seeds on vasorelaxation and myocardial infractions. PURPOSE: Therefore, an integrated metabolomics profiling technique was used to investigate possible pathways of C. lanatus in isoproterenol (ISO)-induced myocardial infarction (MI). Isoproterenol causes long-term cardiac hypertrophy by causing cardiomyocyte compensatory loss, eventually leading to heart failure. METHODS: In vitro models of vasoconstriction, atrium, and in vivo models of invasive blood pressure measurement and isoproterenol (ISO) induced cardiac hypertrophy in rats were used to understand underlying mechanistic by LC-MS/MS based dynamic metabolomics analysis of the serum and heart samples to be investigated the effect of ethanolic extract of C. lanatus (Cl.EtOH). RESULTS: Cl.EtOH exhibited vasorelaxant, negative chronotropic, and inotropic effects in in-vitro models whereas, a potent hypotensive effect was observed in normotensive rats. The Cl.EtOH protected the animals from ISO-induced myocardial infarction (MI) with therapeutic interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, biochemical assays, and metabolomic profiling of serum and heart tissues. CONCLUSIONS: For the first time, our study confirmed that C. lanatus seeds (Cl.EtOH) possess significant antihypertensive and prevent ISO-induced myocardial infarction. These findings comprehensively demonstrated mechanistic insights of Cl.EtOH in vasorelaxation and myocardial infarction. The current study provides evidence for further mechanistic studies and the development of C. lanatus seeds as a potential therapeutic intervention for patients with cardiovascular disorders.

Metabolomics analysis delineates the therapeutic effects of hydroethanolic extract of Cucumis sativus L. seeds on hypertension and isoproterenol-induced myocardial infarction.

Cucumis sativus L., widely cultivated as an edible vegetable. Its seeds are well reputed for cardiovascular preventive properties. However, the mechanisms underlying for cardiovascular protection of C. sativus are still unidentified. Therefore, this study utilized a metabolomics approach to investigate putative mechanisms of C. sativus seeds in myocardial infarction (MI) and in vitro models of vasoconstriction, atrium, and invasive blood pressure measurement. Results showed that Cu.EtOH extract showed a vasorelaxant response with potent hypotensive effect in normotensive rats and L-NAME induced hypertension. Cu.EtOH caused a negative inotropic and positive chronotropic effect on the atrium. Cu.EtOH protected the animals from ISO-induced myocardial infarction (MI) interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, and biochemical assays. The metabolomics data suggested that Cu.EtOH mainly affected amino acid metabolism, BCAA degradation, ketone bodies degradation, and oxidative stress. Our study showed that Cu.EtOH suppressed inflammation with a strong anti-myocardial infarction impact. Additionally, our findings indicated Cu.EtOH reverted the amino acid metabolism, BCAA, and ketone bodies degradation. The findings show the antihypertensive mechanism of Cu.EtOH may include the modulation of endothelium-derived relaxing factor (EDRF) produced from nitric oxide (NO) and is connected with vascular endothelial function. C. sativus seeds, in particular, played a pivotal role in the treatment of myocardial and vascular disorders by enhancing the EDRF mechanism, energy generation, and antioxidant capacity. In summary, our findings showed the mechanistic insights on the therapeutic potential of C. sativus seeds for cardiovascular disorders.

Scientific basis for medicinal use of Citrullus lanatus (Thunb.) in diarrhea and asthma: In vitro, in vivo and in silico studies.

BACKGROUND: Citrullus lanatus (Thunb.) is a member of the Cucurbitaceae family, commonly farmed as an edible vegetable around the globe. It has been used in traditional therapies in addition to nutritional advantages. Traditional herbal practitioners employ C. lanatus seeds to treat gastrointestinal, respiratory, and urinary diseases in Pakistan and India. However, more investigation is needed to understand the effect of C. lanatus seeds on treating gastrointestinal, respiratory, and urinary disorders. PURPOSE: This research aimed to use network pharmacology and molecular docking to understand multi-target mechanisms of C. lanatus seeds against asthma and diarrhea and to validate its effects using biological tests to investigate antispasmodic and bronchodilator capabilities. METHODS: The ground seeds of C. lanatus were extracted in hexane, dichloromethane, ethanol, and aqueous for sequential extracts. The bioactive components in sequential extracts of C. lanatus seeds were identified using LC ESI-MS/MS, and specific compounds were quantified using HPLC. The quantified bioactive compounds of C. lanatus were subjected to in silico studies for network pharmacology and molecular docking to elucidate their role in antispasmodic and bronchodilator properties. The sequential extracts were tested on isolated rabbit tissue, i.e., jejunum, trachea, and urinary bladder. The antiperistalsis, antidiarrheal and antisecretory studies were also performed in animal models. RESULTS: In silico studies indicate that bioactive chemicals from sequential extracts of C. lanatus seeds interfere with asthma and diarrhea-associated pathogenic genes. Those are members of calcium mediate signaling, cholinergic synapse, regulation of cytosolic calcium concentration, smooth muscle contraction, and inflammatory responses. It was also found that rutin, quercitrin, stearic acid, umbelliferone, and kaempferol were stronger binding to voltage-gated calcium channels and muscarinic M3 receptor, thus exerting calcium channel blocker activity and cholinergic receptor stimulant response. On isolated jejunum, trachea, and urinary preparations, sequential extracts of C. lanatus seeds elicited the spasmolytic response and showed the relaxation of spastic contractions of K+ (80 mM) and carbachol (1 µM). Furthermore, it induced a non-parallel rightward shift in calcium concentration-response curves with suppression. In animal models, C. lanatus seed extracts exhibited partially or completely antiperistalsis, antidiarrheal, and antisecretory effects. CONCLUSION: Thus, Citrullus lanatus had therapeutic benefits by modulating the contractile response through calcium-mediated signaling target proteins, hence exerting bronchodilator and antidiarrheal properties. The current study provides evidence for further mechanistic studies and the development of C. lanatus seeds as a potential therapeutic intervention for patients with gastrointestinal, respiratory, and urinary disorders.

Phytochemical Profile, Biological Properties, and Food Applications of the Medicinal Plant Syzygium cumini.

Syzygium cumini, locally known as Jamun in Asia, is a fruit-bearing crop belonging to the Myrtaceae family. This study aims to summarize the most recent literature related to botany, traditional applications, phytochemical ingredients, pharmacological activities, nutrition, and potential food applications of S. cumini. Traditionally, S. cumini has been utilized to combat diabetes and dysentery, and it is given to females with a history of abortions. Anatomical parts of S. cumini exhibit therapeutic potentials including antioxidant, anti-inflammatory, analgesic, antipyretic, antimalarial, anticancer, and antidiabetic activities attributed to the presence of various primary and secondary metabolites such as carbohydrates, proteins, amino acids, alkaloids, flavonoids (i.e., quercetin, myricetin, kaempferol), phenolic acids (gallic acid, caffeic acid, ellagic acid) and anthocyanins (delphinidin-3,5-O-diglucoside, petunidin-3,5-O-diglucoside, malvidin-3,5-O-diglucoside). Different fruit parts of S. cumini have been employed to enhance the nutritional and overall quality of jams, jellies, wines, and fermented products. Today, S. cumini is also used in edible films. So, we believe that S. cumini's anatomical parts, extracts, and isolated compounds can be used in the food industry with applications in food packaging and as food additives. Future research should focus on the isolation and purification of compounds from S. cumini to treat various disorders. More importantly, clinical trials are required to develop low-cost medications with a low therapeutic index.

Syzygium cumini (L.) Skeels extracts; in vivo anti-nociceptive, anti-inflammatory, acute and subacute toxicity assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels has been extensively used in the ancient medical system of Pakistan, India, Bangladesh, and Sri Lanka to combat diabetes, inflammation, and renal disorders. These health-promoting aspects of S. cumini are related to bioactive metabolites such as phenolic acids, anthocyanins, tannins, and flavonoids. AIM OF THE STUDY: Earlier to this study, we have reported S. cumini extracts as potential sources of bioactive compounds bearing antioxidant and anti-inflammatory properties. However, prior further suggesting S. cumini fruit extracts for consumption against inflammatory disorders, it was mandatory to validate the claim and explore toxicity of the extracts. This study aims to determine the in vivo anti-nociceptive, anti-inflammatory, acute, and subacute toxicity properties of S. cumini crude extracts, followed by identifying and quantifying bioactive metabolites. MATERIAL AND METHODS: In the present study, the anti-nociceptive and anti-inflammatory potential of S. cumini sequential crude extracts were evaluated using formalin and glutamate-induced paw licking method in mice. The acute and sub-acute toxicity assessment of active extract was performed by oral administration in rats. An acute toxicity trial was performed with two different doses, i.e., 2000 mg/kg and 3000 mg/kg for consecutive 14 days, whereas a sub-acute toxicity study was conducted at doses of 750 mg/kg and 1500 mg/kg for the next 28 days. Identification of bioactive compounds was performed using HPLC, and at the end, in silico docking calculations of identified compounds were performed. RESULTS: The 100% methanolic extract (SCME) protected the mice from painful stimulation of formalin and glutamate in a dose-dependent manner with the maximum effect of 49% and 67% at 200 mg/kg, respectively, followed by moderate and non-influential effects of 50% methanolic extract and dichloromethane (DCM) extracts when compared to control, i.e., normal saline. The results of acute toxicity recorded LD50 of SCME over 3000 mg/kg, and no antagonistic effects were recorded during the subacute study when SCME dispensed at the rate of 750 mg/kg and 1500 mg/kg. SCME was found to induce no adverse effects to kidney, heart, liver, spleen, and paired lungs examined by hematological, serum biochemical, histological analysis. HPLC analysis of S. cumini 100% methanolic extracts revealed the presence of delphinidin 3-glucoside, peonidin-3,5-diglucoside, scopoletin, and umbelliferone at the concentration of 127.4, 2104, 31.3, 10.4 µg/g whereas in 50% methanolic extract, the quinic acid, catechin, and myricetin were present at the concentration of 54.9, 63.7, 12.3 µg/g, respectively. Umbelliferone and scopoletin are newly reported compounds in the present study. In silico docking calculations of these compounds indicated the potential of anti-nociceptive and anti-inflammatory activities. CONCLUSIONS: These findings validate that S. cumini fruit extracts are a rich source of bioactive compounds that needs to be considered to enhance biological activities with lesser side effects.

The Chemical Composition and Health-Promoting Effects of the Grewia Species-A Systematic Review and Meta-Analysis.

Globally grown and organoleptically appreciated Grewia species are known as sources of bioactive compounds that avert the risk of communicable and non-communicable diseases. Therefore, in recent years, the genus Grewia has attracted increasing scientific attention. This is the first systematic review which focusses primarily on the nutritional composition, phytochemical profile, pharmacological properties, and disease preventative role of Grewia species. The literature published from 1975 to 2021 was searched to retrieve relevant articles from databases such as Google Scholar, Scopus, PubMed, and Web of Science. Two independent reviewers carried out the screening, selection of articles, and data extraction. Of 815 references, 56 met our inclusion criteria. G. asiatica and G. optiva were the most frequently studied species. We found 167 chemical compounds from 12 Grewia species, allocated to 21 categories. Flavonoids represented 41.31% of the reported bioactive compounds, followed by protein and amino acids (10.7%), fats and fatty acids (9.58%), ash and minerals (6.58%), and non-flavonoid polyphenols (5.96%). Crude extracts, enriched with bioactive compounds, and isolated compounds from the Grewia species show antioxidant, anticancer, anti-inflammatory, antidiabetic, hepatoprotective/radioprotective, immunomodulatory, and sedative hypnotic potential. Moreover, antimicrobial properties, improvement in learning and memory deficits, and effectiveness against neurodegenerative ailments are also described within the reviewed article. Nowadays, the side effects of some synthetic drugs and therapies, and bottlenecks in the drug development pathway have directed the attention of researchers and pharmaceutical industries towards the development of new products that are safe, cost-effective, and readily available. However, the application of the Grewia species in pharmaceutical industries is still limited.

Cucumis sativus L. Seeds Ameliorate Muscular Spasm-Induced Gastrointestinal and Respiratory Disorders by Simultaneously Inhibiting Calcium Mediated Signaling Pathway.

Cucumis sativus L. is globally cultivated as an edible vegetable. Besides its nutritional benefits, it is used in traditional medicines against various ailments. The current study was designed to elucidate the multi-target mechanisms of a C. sativus seeds extract against asthma and diarrhea using network pharmacology along with a molecular docking approach. Furthermore, in-vitro and in-vivo experiments were conducted to verify the mechanistic insight of in silico studies. LC-ESI-MS/MS was performed to identify the bioactive compounds in the extract; later, some compounds were quantified by HPLC. C. sativus seed. EtOH has kaempferol in higher concentration 783.02 µg/g, followed by quercetin (693.83 µg/g) and luteolin (617.17 µg/g). In silico studies showed that bioactive compounds interfered with asthma and diarrhea-associated target genes, which are members of calcium-mediated signaling to exert a calcium channel blocker activity. The seeds extract exerted a concentration-dependent spasmolytic response on isolated jejunum, trachea, and urinary bladder preparations and caused relaxation of spastic contraction of K+ (80 mM) with suppressed calcium concentration-response curves at dose 0.3 and 1 mg/mL. It also showed antiperistalsis, antidiarrheal and antisecretory activity in animal models. Thus, C. sativus seeds have therapeutic effects by regulating the contractile response through a calcium-mediated signaling pathway.

Nutritional perspectives for the prevention and mitigation of COVID-19.

Worldwide, there is an array of clinical trials under way to evaluate treatment options against coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2. Concurrently, several nutritional therapies and alternative supportive treatments are also being used and tested to reduce the mortality associated with acute respiratory distress in patients with COVID-19. In the context of COVID-19, improved nutrition that includes micronutrient supplementation to augment the immune system has been recognized as a viable approach to both prevent and alleviate the severity of the infection. The potential role of micronutrients as immune-boosting agents is particularly relevant for low- and middle-income countries, which already have an existing high burden of undernutrition and micronutrient deficiencies. A systematic literature review was performed to identify nutritional interventions that might prevent or aid in the recovery from COVID-19. The PubMed, ScienceDirect, Cochrane, Scopus, Web of Science, and Google Scholar databases were searched electronically from February to April 2020. All abstracts and full-text articles were examined for their relevance to this review. The information gathered was collated under various categories. Deficiencies of micronutrients, especially vitamins A, B complex, C, and D, zinc, iron, and selenium, are common among vulnerable populations in general and among COVID-19 patients in particular and could plausibly increase the risk of mortality. Judicious use of need-based micronutrient supplementation, alongside existing micronutrient fortification programs, is warranted in the current global pandemic, especially in low- and middle-income economies.

Pharmacological exploration of traditional plants for the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is clinically characterized as memory deficits, altered behavior and impaired cognitive functions. The most important risk factor for AD is aging and mounting. Evidences suggested in different studies that traditionally used plants in Asia, China, and Europe significantly affect aging and AD involved neurodegeneration pathways. Research into ethnobotanicals for impaired memory and cognition has been burgeoned in last decades. The inclusion and exclusion criteria for the plant selection were based on reputed herbs recommended for treatment of neurological disorders and their scientific validation to cure neurodegenerative disorders. A range of traditional plants imparts effects via acetylcholinesterase activity, ß-amyloid peptide formation in plaques, neurotrophic factors and through antioxidant activity. On one side preclinical investigations identified promising drug candidates for AD, on the other side, clinical evidences are still pending. Presently, according to WHO, around more than 80% world population relay on natural remedies to cure their health related issues. Plants contain rich source of primary and secondary metabolites for improving health problems. Pharmaceutical industry is facing intriguing challenges like elevated cost and unendurable risk management due to the high burden of neurodegenerative disorders. A significant shift of drug discovery is being witnessed from synthetic moieties to herbal formulation.

Antiplatelet Aggregation, Cardiotonic, Anti-Inflammatory, Antioxidant, and Calcium Channel Antagonistic Potentials of Nepeta ruderalis Buch.

The objective of this study was to authenticate the ethnobotanical claims of the Nepeta ruderalis Buch.-Ham. (N. ruderalis) extract in the traditional system of medicine. Crude extract was prepared via a simple maceration process. DPPH free radical scavenging and carrageenan-induced rat paw edema models were used to monitor antioxidant and anti-inflammatory responses of the N. ruderalis extract. Furthermore, it was tested for antiplatelet aggregation, cardioprotective, and calcium channel antagonistic activities via standard documented protocols. The N. ruderalis extract exhibited 80.82% antioxidant activity (IC50 = 207.51 ± 4.36 µg) while the anti-inflammatory response was significant (p < 0.05 to p < 0.01) at 50 mg/kg (45.58%) and 100 mg/kg (60.90%) doses. Moreover, it was found to inhibit platelet aggregation (IC50 = 1.06 and 0.91 mg/mL) and, in addition, to increase the force of contraction at the concentration of 3.0-10 mg/mL with a decrease in the heart rate on isolated paired atria (EC50 = 11.78 mg/mL). Relaxant activity was observed on the isolated rabbit jejunum (EC50 = 0.96 mg/mL) and trachea (EC50 = 0.89 mg/mL). However, in a cumulative way, an 80-millimolar potassium-induced contraction was evaluated (EC50 = 1.31 mg/mL). The N. ruderalis extract exhibited antioxidant, anti-inflammatory, platelet aggregating, cardiotonic, and calcium channel antagonistic activities, therefore proving scientifically its effectiveness in the traditional system of medicine.